Research:
Neuropharmacology of benzodiazepine tolerance and physical dependence Pharmacology of neurally released GABA
Brain microdialysis of GABA from the Substantia Nigra
Rotational Behavior
Benzodiazepine (BZ) anxiolytic-sedative-hypnotics like chlordiazepoxide (CDP), diazepam or triazolam are among the most widely prescribed drug classes worldwide. Chronic use is associated with tolerance and physical dependence evidenced by a withdrawal syndrome of CNS hyperexcitability when abruptly stopped. Our lab has developed several animal models to reliably produce and quantify these phenomena in rats using CDP. These models have been used to study neuronal mechanisms of withdrawal and to quantitatively compare the physical dependence potential of other anxiolytic-sedative-hypnotics relative to the CDP standard. A GABA hypothesis of reduced or hypoeffective neurotransmission has been advanced by our lab and others. We found no change in GABA-gated chloride flux suggesting that the hypoeffective state of GABA transmission might result from pre-synaptic adaptations due to reduced GABA release. Limitations of current approaches to study neurally released GABA led to a shift in our research focus to develop better methods. Current work is to develop a combined neurochemical-behavioral whole animal bioassay for neurally released GABA. The strategy is to monitor neurally released GABA in the subtantia nigra by microdialysis and rotational behavior following unilateral electrical stimulation of the GABA-ergic striatonigral input in awake freely-moving rats.